Circulating PD1+Vd1+gd T Cell Predicts Fertility in Endometrial Polyp Patients of Reproductive-Age
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ORIGINAL RESEARCH
published: 15 June 2021
doi: 10.3389/fimmu.2021.639221
Circulating PD1+Vd1+gd T Cell
Predicts Fertility in Endometrial
Polyp Patients of Reproductive-Age
Xiao-Hong Li 1†, Mei-Yin Lu 2†, Yi-jia Li 3,4, Zong-hua Liu 4, Zhi-nan Yin 3,4, Bin Liu 2*
and Yang-zhe Wu 3*
1 Department of Obstetrics and Gynecology, Shenzhen Baoan Women’s and Children’s Hospital, Jinan University,
Shenzhen, China, 2 Department of Biobank, Shenzhen Baoan Women’s and Children’s Hospital, Jinan University,
Shenzhen, China, 3 Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan
University), Zhuhai, China, 4 The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University,
Guangzhou, China
Clinically, immune cell function is correlated with pathogenesis of endometrial polyp (EP) and
Edited by: infertility of women of reproductive-age. However, the underlying immune cell hallmark in EP
Sha Wu,
Southern Medical University, China
patients remains unclear. Here, we focused on analyzing circulating immune cells, and
Reviewed by:
attempted to reveal the correlation between peripheral immune cell functional phenotypes
Zhuoran Zhang, and fertility in EP patients. Through comparison of circulating CD4+/CD8+ T cells, NK cells,
City of Hope National Medical Center,
and gd T cells between 64 EP patients and 68 healthy females, we found that gd T cells, but
United States
Wei Zhu, not CD4+/CD8+ T cells and NK cells, were immunologically correlated with conception rate
Southern Medical University, China and conception interval time. Specifically, total gd T cells and the Vd1+PD1+ gd T
*Correspondence: subpopulation decreased whereas the Vd1/Vd2 ratio increased in EP patients compared
Bin Liu
gz12liubin@163.com
to healthy controls. Moreover, the patients with the higher Vd1/Vd2 ratio (median value
Yang-zhe Wu equals 1.04) had a poorer fertility and longer interval time of conception (210 days versus
tyzwu@jnu.edu.cn
158 days for control). Meanwhile, higher Vd1+PD1+ gd T cell proportion (median equals 15.7)
†
These authors have contributed
was positively correlative with both higher conception rate and shortened median
equally to this work and
share first authorship conception interval time (130 days for Vd1+PD1high group versus 194 days for
Vd1+PD1low group). Notably, in healthy controls, both Vd1/Vd2 ratio and Vd1+PD1+ gd T
Specialty section: cell proportion correlated with pregnancy rate oppositely, comparing to EP patients.
This article was submitted to
Alloimmunity and Transplantation,
Together, our results suggested that imbalanced gd T cell population occurred in EP
a section of the journal patients, and that Vd1/Vd2 ratio and PD-1 expression of Vd1+ gd T cells could be potentially
Frontiers in Immunology
developed into valuable predictors for fertility in EP patients.
Received: 08 December 2020
Accepted: 19 April 2021 Keywords: endometrial polyp, fertility, biomarker, gd T cells, PD-1
Published: 15 June 2021
Citation:
Li X-H, Lu M-Y, Li Y-j, Liu Z-h,
Yin Z-n, Liu B and Wu Y-z (2021)
INTRODUCTION
Circulating PD1+Vd1+gd T Cell
Predicts Fertility in Endometrial Polyp
The dynamic equilibrium is one type of fundamental features of human endometrium, for example,
Patients of Reproductive-Age. rebalancing between periodical proliferation and apoptosis, tissue breakdown, and repairment, which
Front. Immunol. 12:639221. serves the major and basic function of regulating embryo implantation (1). Therefore, the excessive
doi: 10.3389/fimmu.2021.639221 proliferation of endometrium would occur in certain condition of inductions, and this could adversely
Frontiers in Immunology | www.frontiersin.org 1 June 2021 | Volume 12 | Article 639221
Li et al. PD1+Vd1+gd T Cell Predicts Fertility
induce diseases if it keeps getting worse. Endometrial polyp (EP) is developed into the prediction biomarkers for pregnancy ability
one consequence of excessive proliferation of endometrium in endometrial polyp patients of reproductive-age. This proof-of-
commonly occurring in women of reproductive-age. Clinically, concept work not only will benefit further investigation of the
EP is a type of benign lesion in women with focal growth of the underlying pathogenesis of EP, but also could promote
endometrial glands and stroma (2). EP affects approximately 7.8– development of immune cell phenotype biomarkers predicting
34.9% of reproductive women and usually impairs fertility (3, 4). pregnancy ability in EP of reproductive age.
Previous reports showed that assisted reproductive technology such
as in vitro fertilization is required for 11–45% EP patients (5, 6). In
addition to fertility impairment, abnormal uterine bleeding (AUB)
is another common symptom of EP, which relates to aberrant tissue
MATERIALS AND METHODS
damage and repair in endometrium. Currently, it generally Enrollment and Follow-Up of
recognized that EP can negatively affect the quality of life, such as
Research Cohorts
physical, emotional, sexual, and professional aspects of the lives of
The research cohort of this study was shown in Figure 1. Briefly, 64
women (7).
EP patients with 20~40 years old routinely diagnosed by
As for EP diagnosis, transvaginal ultrasonography (TVUS) is a
hysteroscopy (1), ultrasonic imaging, and pathological
reliable approach, and the Color-flow or Power Doppler technology
examinations were enrolled at Shenzhen Baoan Women’s and
can further improve the diagnostic accuracy of TVUS (1). Blind
Children’s Hospital of Jinan University between June and
dilation and curettage or biopsy is only used to exclude the
December 2018. Clinically, the common treatment of EP patients
malignant polyps (1). For small or asymptomatic polyps,
is to apply hysteroscopic polypectomy. Therefore, to evaluate
conservative management rather than medical treatments
peripheral immune cell phenotypes, 2 ml of heparin anticoagulant
(GnRHa or hormonal therapy) is generally adopted clinically (2).
blood was collected before operation of polypectomy. At the same
For AUB or infertility patients, however, surgeries including blind
dilation and curettage, hysteroscopic polypectomy, and even
hysterectomy could be applied to remove polyps (1). Published
clinical data showed that polypectomy could effectively relieve
symptoms of EP (3, 4). Nevertheless, infertility is a common issue
in EP patients of reproductive-age (5). Currently, the underlying
mechanism of EP occurrence or development remains to be fully
illustrated. Moreover, the biomarkers associating with fertility in EP
patients are urgently needed clinically, which could particularly help
the EP patient who is planning pregnancy.
Although the precise pathogenesis of EP remains largely unclear,
high risk factors such as aging, hypertension, obesity, and drug (e.g.
tamoxifen) usage were reported to contribute to development of EP
(1). Increasingly, immunological imbalance or dysfunction has been
recognized as one of important factors causing EP (6–8). Black et al.
(2013) reported that inflammatory lesion associated with infiltrated
mast cells in EP tissue plays important roles in inducing local
immune disturbances (8). Moreover, the circulating monocytes of
EP patients can secrete high levels of TNF, IL-1b, IL-6, and IL-23,
which could impair fertility (9). In addition, endometrial
inflammation (10, 11) or infection of chlamydia trachomatis (12)
are also prone to induce AUB and subfertility (10). Altogether, local
inflammation and dysfunctional cellular immune environment are
believed to play important roles in etiology, pathophysiology, and
infertility or poor pregnancy outcomes in EP patients.
In the present study, we focused on functional phenotype
alterations of circulating immune cells (CD4+/CD8+ T cells, NK,
and gd T cells) in EP patients, and aimed to discover immune cell
related biomarkers associating with pregnancy ability. We used
our previously established methodology (13) to globally evaluate
phenotypes of peripheral immune cells, and compare alterations
between healthy populations and EP patients of reproductive
age. Then we analyzed the immunological relevance between the FIGURE 1 | The flow chart showing how this study was designed. In our
work, 64 EP patients and 68 healthy population (control group) were enrolled
immune cell phenotypes and pregnancy outcome, indicating that
to collect samples and perform subsequent analyses.
circulating PD1+Vd1+gd T cell and the Vd1/Vd2 ratio could be
Frontiers in Immunology | www.frontiersin.org 2 June 2021 | Volume 12 | Article 639221
Li et al. PD1+Vd1+gd T Cell Predicts Fertility
time, 68 healthy females of reproductive age who were going to EP patients and healthy controls were described as Table 1.
receive pre-pregnancy medical examinations were enrolled in this Given the unique immune function of gd T cells, it’s of significant
study as well. The excluding criteria of the healthy cohort included importance to detect how gd T cells were proportionally altered
endometrial polyps, ovary morbidities, infertility, leiomyoma, and in patients. We thus compared cell proportion of gd T cells
other tumors. Similarly, 2 ml of peripheral blood was collected for (Figures 2 and 3) between control and EP groups using flow
subsequent analyses. cytometry. It showed that, compared with healthy populations,
As for follow-up, all enrolled people were scheduled to come EP patients have statistically lower amount of gd T cells
back for routine examinations every 3 months. The pregnancy (Figure 2B). We further analyzed statistical alterations of gd T
status was verified by serum human chorionic gonadotropin subsets. It showed that EP has higher Vd1 cell proportion
(HCG) and ultrasound, and the first day of the last menstrual (57.47± 3.62, n = 64) comparing with the control population
period (LMP) was recorded. The pregnancy status of two cohorts (42.72± 2.71, n = 68), but the lower Vd2 cell proportion (42.32±
was followed up until 2019 December. Then the association 3.63) comparing with the control (57.2± 2.72). This thus led to a
between peripheral immune cell functional phenotypes and significant elevation of the Vd1/Vd2 ratio, from 1.49± 0.41 for
pregnancy rate was analyzed. the control to 7.16± 1.77 for the EP patients (Figure 2C). Further
This study was approved by the Ethics Committee of flow analyses on Vd1+gd T cells indicated that Vd1+NKP30+ gd T
Shenzhen Baoan Women’s and Children’s Hospital, Jinan cells increased while Vd1+PD-1+ gd T cells decreased in patients
University (IRB No: LLSC-2018-08-01). (Figure 3A), and representative flow gating graphs are shown in
Supplementary Figure 1. As for Vd2+gd T cells, we observed
Immune Cell Phenotype Analyzing by that Vd2+NKG2D+ gd T cells decreased while Vd2+NKP30+ gd T
Flow Cytometry cells increased in EP patients (Figure 3B).
Collected peripheral blood samples were analyzed using flow Here, we also compared changes of ab T and NK cells between
cytometry. Briefly, peripheral blood mononuclear cells (PBMCs) control and EP groups (Supplementary Figures 2, 3) by checking
were isolated using Ficoll-Paque centrifugation, then stained by expressions of function-related surface marker receptors. Here,
the following antibodies: PerCP-CY5.5-conjugated anti-CD3; CCR7 and CD45RA were used to determine CD4+ and CD8+ T
APC-conjugated anti-CD4; FITC-conjugated anti-CD45RA; cell differentiation, it indicated that naïve (CD4+CCR7+CD45RA+)
PE-conjugated anti-CD25 and anti-Vd2; PE-CY7-conjugated and central memory (CM, CD4+CCR7+CD45RA−) populations
anti-CD28 and anti-NKG2D; BV421-conjugated anti-56, anti- statistically increased in EP patients, and terminal differentiated
127, anti-CD194, and anti-TCRgd; BV510-conjugated anti-CD8 effector memory (EMRA, CD4+CCR7−CD45RA+) populations
and anti-NKP46; Alexa Fluor 647-conjugated anti-CCR7 and statistically decreased in patients (Supplementary Figure 2A). As
anti-CXCR5; Alexa Fluor 484-conjugated anti-CD183, and for CD8+ T cells, we found that CM subset significantly increased
BB515-conjugated anti-PD-1. The antibodies were bought while EMRA subset decreased in patients compared with control
from BD biosciences. Samples were then analyzed using BD group (Supplementary Figure 2B).
LSR Fortessa (BD Biosciences) at Shuangzhi Purui Medical Given helper T (Th, CD3+CD4+CXCR5−) and follicular
Laboratory Co., Ltd. (China), and data was analyzed using helper T (Tfh, CD3+CD4+CXCR5+) cells are all differentiated
FlowJo 10.1 software (Tree Star Inc., Ashland, OR, USA). from the naïve CD4+ T cells, we also compared the proportional
alterations of these cells between patients and healthy controls.
Statistical Analysis We found that, compared to the control group, the ratios of Th1/
SPSS 25.0 (IBM) was used to process and analyze the data. For Th2, (Th1+Th17)/Th2, and Tfh1/Tfh2 were significantly higher
analyzing the difference in immune cells and its subsets between in patients (Supplementary Figures 2C, D). Additionally, we
patients and controls, Mann-Whitney U tests were performed. also analyzed double negative T cells (CD3+CD4−CD8−) and
The pregnancy rate and median pregnancy time (MPT) between CD56+NKP30+ NK cells, it revealed that the double negative T
different groups were analyzed by Kaplan-Meier Survival Curve, cells were statistically increased in patients compared with the
log-rank test, and Cox regression analysis by adjusting for age, healthy population, and meanwhile CD56+NKP30+ NK cells
history of infertility, and the number and diameter of were statistically lowered (Supplementary Figure 3).
endometrial polyp in EP patients. All tests were two sided, and
the level of significance was set at 0.05. Statistical figures were Vd1+PD1+ gd T Cells Associate With
produced by GraphPad Prism7.0 (GraphPad Software, USA).
Pregnancy Rate of EP Patients
To uncover which immune cell subset was the most important
factor associating with pregnancy rate of EP patients, we further
RESULTS analyzed correlation between pregnancy rate and immune cell
subsets in 49 EP patients, as shown in Figure 4 and
Overall Immune Function Profiles of gd T, Supplementary Figure 3. We could clearly see that, among 15
ab, and NK Cells in EP Patients immune cell subsets/parameters, only Vd1+PD1+ gd T cell and the
In our work, 64 EP patients were enrolled, and 68 healthy women Vd1/Vd2 ratio were closely relevant with pregnancy rate of EP
were included as control group, and the cohort diagram is shown patients (Table 2, Figure 4A). Specifically, in peripheral blood of
in Figure 1. The clinical and demographic characteristics of these EP patients, Vd1+ subset is reversely correlated with pregnancy
Frontiers in Immunology | www.frontiersin.org 3 June 2021 | Volume 12 | Article 639221
Li et al. PD1+Vd1+gd T Cell Predicts Fertility
TABLE 1 | Clinical and demographic characteristics of endometrial polyp TABLE 1 | Continued
patients and healthy controls.
Variables Cases, n (%) Controls, n (%) Pa
a
Variables Cases, n (%) Controls, n (%) P
≤1 38 (59.4) –
All subjects 64 (100) 68 (100) Pregnancy time after follow-up (days) 185 ± 119 142 ± 131 0.074
Age, years Pregnancy after follow-up 27 (42.2) 35 (51.5) 0.372
7 10 (15.6) 18 (26.5)
(adjusted relative risk (RR) = 0.330, 95% CI = 0.137–0.791). It
Dysmenorrhea 53 (82.8) 37 (60.3)
Li et al. PD1+Vd1+gd T Cell Predicts Fertility
A
B
C
FIGURE 2 | Representative flow graphs (A, B) and statistical analysis results (C). (C) Statistical comparison of gd T cell proportions in CD3+ T cells, Vd1 and Vd2
subsets in gd T cells, and the Vd1+/Vd2+ ratio between the healthy group and the patient group. **P < 0.01. ***P < 0.001.
peripheral immunity affects pregnancy ability is yet to be fully CD3 + gd + Vd2 + , Vd1 + /Vd2 + ratio, CD3 + gd + Vd2 + NKG2D + ,
understood. Therefore, in this prospective study, we focused on CD3+gd+Vd2+PD1+, CD3+gd+Vd2+NKP30+,
characterizing immune profiles/phenotypes of circulating immune CD3+gd+Vd2+NKP46+, CD3+gd+Vd1+NKG2D+,
cells, such as CD4+ T cells, CD8+ T cells, NK cells, and gd T cells. As CD3+gd+Vd1+PD1+, CD3+gd+Vd1+NKP30+, and
for CD4+ and CD8+ T cells, we checked 22 parameters, including CD3+gd+Vd1+NKP46+. Among these 44 immune parameters, we
CD3+, CD3+CD4+, CD3+CD8+, CD3+CD4+CD8+, only observed 16 parameters had statistical difference (refers to
CD3+CD4−CD8−, CD3+CD4+/CD3+CD8+, CD3+ Figures 2, 3 and Supplementary Figures 2, 3). Such results
CD4+CD45RA+CCR7+, CD3+CD4+CD45RA+CCR7−, suggested that only partial immune parameters of peripheral
CD3 + CD4 + CD45RA − CCR7 + , CD3 + CD4 + CD45RA − CCR7 − , immune cells (CD4+, CD8+ T cells, NK cells, and gd T cells)
CD3+CD4+CD28−, CD3+CD4+CD28+, CD3+CD4+CD25+CD127−, would be relevant to pregnancy of reproductive-age of women in
CD3 + CD8 + CCR7 + CD45RA + , CD3 + CD8 + CCR7 − CD45RA + , the context of endometrial polyp (EP). Given this context, we
CD3 + CD8 + CCR7 + CD45RA − , CD3 + CD8 + CCR7 − CD45RA − , further conducted correlation analyses between immune
CD3 + CD8 + CD28 − , CD3 + CD8 + CCR7 − CD45RA − CD127 + , parameters with statistical difference and pregnancy rate, and the
CD3+CD8+CCR7−CD45RA+CD127+, CD3+CD8+ results surprisingly showed that only two parameters Vd1+/Vd2+
CCR7− CD45RA− CD127− , and CD3+ CD8+ CCR7− CD45RA+ ratio and CD3+gd+Vd1+PD1+ T cell proportion, rather than all
CD127− T cells. Meanwhile, we checked 10 parameters for NK other parameters, were immunologically correlated with
cells, including CD3+CD56+ (TNK), CD3−CD56+, CD3−CD56high, pregnancy rate.
CD3−CD56low, (CD3−CD56high)/(CD3−CD56low), It should be mentioned here that, gd T cell along with ab T
CD3 − CD56 + CD94 + KIR − , CD3 − CD56 + CD94 − KIR + , CD3 − cell are two major subsets of T lymphocytes. Different from ab
CD56+NKG2D+, CD3−CD56+NKP30+, and CD3−CD56+NKP46+. T cell, gd T cell only constitutes 1–10% of peripheral blood T
Moreover, we further analyzed phenotypes of circulating gd T cells, lymphocytes in human, and majority of cells locates in tissue
the 12 parameters contained CD3 + gd + , CD3 + gd + Vd1 + , mucosa (19), such as uterine endometrium (20). Unlike ab T
Frontiers in Immunology | www.frontiersin.org 5 June 2021 | Volume 12 | Article 639221
Li et al. PD1+Vd1+gd T Cell Predicts Fertility
A
B
FIGURE 3 | Expressions of crucial receptors of Vd1+ and Vd2+ gd T cells in healthy and EP populations. (A) Comparison analyses of expressions of NKG2D, PD-1,
NKP30, and NKP46 receptors of Vd1 gd T cells acquired by flow cytometry. (B) Expressions of NKG2D, PD-1, NKP30, and NKP46 receptors expressed in Vd2 cell
subset. ns, no significance; **P < 0.01; ***P < 0.001.
cells, the activation of gd T cells is MHC-independent (21). opposite gd T cell phenotype between the EP group and the
Importantly, increasing evidences suggested that gd T cells can control group suggested that the balance between Vd1+ gd T cell
exert strong direct or indirect influences on network of both and Vd2+ gd T cell is quite important for pregnancy of women of
innate and adaptive immunity (22), for instance, activation of reproductive age. However, whether functional difference of gd T
antigen-presenting cells and/or direct stimulation of other cell between two groups led to such opposite phenotype remained
mucosal leukocytes, such as ab T cells and neutrophils (19, to be further verified.
21). Additionally, different gd T cell subset could has opposite Commonly, majority (>50%) of peripheral gd T cells carries
effector functions, for example, Vd1+ gd T cells that are more Vd2 TCR in human (24), therefore, the Vd1+/Vd2+ ratio is less
prone to immune depression, as a contrast, Vd2+ gd T cells than 1 in healthy population. According to our unpublished data,
belongs to cytotoxic subset (23). however, the Vd1+/Vd2+ ratio is commonly and greatly higher
According to relevance analyses, we found the Vd1+/Vd2+ than 1 in cancer patients, implicating with immune suppression
ratio and Vd1+PD-1+ gd T cells increased in EP patients, and effects exerted by Vd1+ gd T cells. As for suppression aspect of
these two parameters of gd T cells were associated with pregnancy Vd1+ gd T cell, it possesses regulatory function just like
rate (time) in reproductive EP patients. Specifically, when the conventional Treg cell. Previous works had also described that
Vd1+/Vd2+ ratio is greater than 1.04, the pregnancy time could be this subset can secrete higher amounts of TGF-b than
delayed for 52 days, from 158 days to 210 days (median conventional Treg, and can potently suppress naïve and
pregnancy time, MPT). As for Vd1+PD-1+ gd T cells, however, effector T cells responses and meanwhile inhibit maturation of
higher expression of PD-1 molecules in Vd1+ gd T cells implicates dendritic cells in tumor (24–26). In addition, since gd T cells at
with better pregnancy rate, significantly reduced MPT from 194 the maternal-fetal during pregnancy are mainly recruited from
days to 130 days, and the threshold valve for Vd1+PD-1+ gd T peripheral blood, it’s logical to hypothesize that circulating gd T
cells in Vd1+ gd T cells was set at 15.7 according to statistical cells would be new markers for postoperative fertility in EP.
median. It’s surprising to note that, in healthy populations Therefore, in healthy population of reproductive age, higher
without EP, however, the statistical calculation indicated that proportion of Vd1+ gd T cell subset, which can produce immune
the pregnancy outcomes associating with Vd1+/Vd2+ ratio and suppressive effects and thus balance cytotoxic effect of Vd2+ gd T
Vd1+PD-1+ gd T cells were opposite comparing to EP. Such cell subset, could facilitate fertilization and subsequent embryo
Frontiers in Immunology | www.frontiersin.org 6 June 2021 | Volume 12 | Article 639221Li et al. PD1+Vd1+gd T Cell Predicts Fertility
A
B
FIGURE 4 | The Kaplan-Meier Curve plotted based on the median values of Vd1+/Vd2+ ratio or Vd1+PD-1+ gd T cells of EP patients. (A) Comparison of pregnancy
rate (MPT) between two groups with above or below Vd1/Vd2 ratio (1.04), or PD-1 expression (15.7%). (B) Comparison pregnancy rate (MPT) between healthy
populations.
TABLE 2 | Analysis of Vd1/Vd2, Vd1+PD1+ gd T cells and pregnancy rate.
Pregnants n (%) MPT (days) Log-Rank p Value RR (95% CI)a Cox model p Value a
Patients
Vd1/Vd2 27 (42.2) 170Li et al. PD1+Vd1+gd T Cell Predicts Fertility
a contrast, because of existence of immune disturbance in EP benefit EP patients. Finally, the present work revealed hallmarks
patients, the clinical relevance between pregnancy rate and the of peripheral gd T cell in reproductive females with and without EP,
Vd1+/Vd2+ ratio as well as PD-1+Vd1+ gd T cell showed to be the and provided a proof-of-concept for discovering immunological
opposite when comparing with the healthy populations. We biomarker for predicting fertility clinically.
believe that systematical immune cell function suppression
contributed crucially to the developed endometrial polyp in
women of reproductive age, especially the imbalanced Vd1+ gd
T cell versus Vd2+ gd T cell in peripheral blood. Moreover, DATA AVAILABILITY STATEMENT
compared to healthy controls, higher proportion of Vd1+ gd T
cell and significantly reduced expression of PD-1 in Vd1+ gd T The raw data supporting the conclusions of this article will be
cell suggested a more potent immune suppression in EP patients, made available by the authors, without undue reservation.
which thus affects pregnancy adversely (lower conception rate
and longer interval time). Therefore, among EP patients, those
have either lower Vd1+/Vd2+ ratio or higher proportion of PD-
ETHICS STATEMENT
1+ Vd1 gd T cell, which suggests less immune suppressive
features of gd T cells, can lead to better outcome on successive The studies involving human participants were reviewed and
pregnancy. Different from healthy controls, PD-1highVd1+ gd T approved by the Shenzhen Baoan Women’s and Children’s
cells could be potentially developed into a biomarker for Hospital, Jinan University (IRB No: LLSC-2018-08-01). The
predicting the required duration of post-operative pregnancy patients/participants provided their written informed consent
for those EP patients who received hysteroscopic polypectomy. It to participate in this study.
should be mentioned that further large scale of EP patients will
be recruited to validate such findings, particularly the clinical
relevance of PD-1+Vd1+ gd T cells in predicting fertility in EP
population of reproductive age. Notably, we only examined AUTHOR CONTRIBUTIONS
circulating immune cells of EP patients, it’s worthy to unveil
whether the infiltrated immune cells including gd T cells (Vd1+/ X-HL: project design, sample collection, follow-up, data analysis,
Vd2+ ratio and PD-1+ Vd1 T) in the endometrium have similar and manuscript drafting. M-YL: sample collection, data analysis,
change pattern to the circulating gd T cell, and the underlying and graphs plotting. Y-jL, Z-hL, and Z-nY: data analysis and
functional features of both circulating and infiltrated gd T cells result discussion. BL: project design and management, data
are of worthy to be further investigated as well. analysis, and manuscript drafting. Y-zW: project design,
In conclusion, the present work suggests the mild imbalance of experimental supervision, data analysis and discussion, and
immune phenotype between Vd2 and Vd1 gd T cells is crucial for manuscript drafting and revision. All authors contributed to
successful pregnancy of healthy women of reproductive age. More the article and approved the submitted version.
importantly, the Vd1/Vd2 ratio could be a common indicator in
both healthy and EP populations of reproductive age to predict the
required duration of pregnancy; ≥1.04 of the Vd1/Vd2 ratio in
healthy women implies shorter MPT, however,Li et al. PD1+Vd1+gd T Cell Predicts Fertility
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